PROJECT SUMMARY ? OMICS CORE The Developmental and Hyperactive Ras Tumor SPORE has been designed to support the research of four different projects, all with the goal of identifying new targeted molecular therapies for NF1 malignancies. NF1 is a RASopathy driven by autosomal dominant mutations in the NF1 gene, which encodes the protein, neurofibromin, a tumor suppressor in specific tissues due to its function as a Ras GTPase Activating Protein (GAP). Loss of neurofibromin in specific tissues leads to increased levels of GTP bound Ras resulting in Ras hyperactivity. Activated Ras increases activity of several signaling networks, many involving kinase pathways such as Raf-MEK-ERK and PI3K-AKT-mTOR. The Omics Core will support the research activities of Projects 1- 4 by integrating state-of-the-art technology and informatics platforms that include: 1. The Genomics Library Lab will receive tumors from each of the four projects that have been curated and characterized in the Biospecimens and Pathology Core. It will be responsible for tumor processing for making libraries for RNAseq, whole exome seq and directed exome seq from FFPE tumors. G-Path will also provide tumors to be used for assessment of kinome activation signatures. 2. The High Throughput Sequencing Facility will provide deep sequencing of RNA and exomes for the projects. 3. The Omics Core bioinformatics group will analyze and annotate all RNAseq and exome sequencing data for transfer to Synapse, the Sage portal for data analysis. 4. Chemical proteomic methods developed to assess the activation state of the tumor kinome en masse will be performed for projects 1-3 for both baseline activity signatures of neurofibromas, MNPST and JMML. In addition, dynamic changes in activation state of the kinome for NF1 malignancies responding to targeted kinase inhibitors will be determined. 5. Modeling of kinome dynamics will be used to define kinome subnetworks that include specific kinases that may present as new therapeutic targets for the treatment of the different NF1 malignancies. The Omics Core will work closely with Sage Bionetworks and the Administrative Core for integrative analysis of the different datasets. Synapse, a web portal maintained by Sage will allow access by SPORE investigators of data obtained by the Omics and Biospecimen Cores, where findings will be annotated and made more broadly useful to all investigators involved in the SPORE. This data management portal will provide a unique resource for accessing and interpreting data generated by the four projects, Biospecimens and Pathology Core and Omics Core.